1. Field of the Invention
The present invention relates to a novel drug combination for more effective treatment of pain, fever, and inflammation with reduced ulcerogenicity.
Particularly, the present invention is concerned with the combination of (a) 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin), and (b) a member selected from phenyl benzoic acid compounds, especially 2-hydroxy-5-(2',4'-difluoro-phenyl) benzoic acid (diflunisal).
The 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin), compound has long been an effective therapeutic agent in the treatment of pain, fever, and inflammation, and has been especially useful in treating rheumatoid arthritis. However, it has long been recognized that use of indomethacin also results in undesirable irritation of the gastrointestinal mucosa, eventually leading, in many cases, to ulceration. All non-steroidal anti-inflammatory agents are also, to a greater or lesser extent, ulcerogenic; and it is hypothesized that a contributing factor to the basic mechanism of gastrointestinal irritation by these agents is the inhibition of prostaglandin production in the gastrointestinal mucosa.
2. Brief Description of the Prior Art
The 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid compound employed in the novel drug combination of the present invention is described in U.S. Pat. No. 3,161,654.
The phenyl benzoic acid compounds employed in the novel drug combination of the present invention are described in U.S. Pat. Nos. 3,674,870 and 3,714,226.
The use of various compounds, particulary salicylic acid derivatives, to combat the gastrointestinal ulceration associated with use of various anti-inflammatory drugs, is known. See, for example, (1) Hanchar et al., "Antiulcer Effect of Aspirin", Gastroenterology, Vol. 72, No. 5, Part 2 (1977) which reports the protective effect of aspirin, sodium salicylate, and aminopyrine when used with indomethacin; (2) British Patent No. 1,483,165 which describes anti-flammatory compositions having decreased gastrointestinal side-effects comprising indomethacin or other anti-inflammatory agents together with salicylic acid or an alkali metal salicylate; (3) U.S. Pat. No. 4,016,268 which describes the use of bismuth subsalicylate co-administered with anti-inflammatory drugs to combat gastric ulceration associated with such drugs; (4) Robert and Asano, Prostaglandins, Vol. 14, No. 2, pp. 333-338 (1977) which describes the use of 16, 16-dimethyl PGE.sub.2 to prevent intestional lesions from indomethacin in experimental animals; (5) Japanese Patent Publication No. 5 3062 839 which discloses the use of mepirizole with non-steroidal anti-inflammatory agents to reduce ulcer formation caused by the latter; (6) Rainsford, Agents and Actions, Vol. 7, 516, pp. 573-577 (1977) which discloses that while the mixture of indomethacin and probenecid is effective in reducing the gastric damage by indomethacin, the effect of aspirin and indomethacin is almost additive; (7) Goburdhum et al. J. Pharma. Methods. Vol. 1, pp. 109-114 (1978) which discloses that copper salicylate is more effective than sodium salicylate in achieving inhibition of the ulcerogenic effects of indomethacin; (8) U.S. Pat. No. 4,066,756 which discloses the use of sodium cromoglycate to inhibit the gastrointestinal irritation caused by indomethacin; and (9) Scrip, Oct. 14, 1973, p. 24, which discloses the use of parsalamide or rimazolium methylsulfate to reduce the ulcerogenic potential of indomethacin. However, unlike the majority of co-administered agents described in the prior art, particularly sodium salicylate and aspirin, the phenyl benzoic acid compounds employed in the present invention are, surprisingly, many times more effective on a molar basis.
Gastric ulceration in the rat has also been shown to be inhibited by salicylic acid or aspirin alone. See Pauls et al., Science, Jan. 2, 1948.